Tablet formulation comprising a glp-1 peptide and a delivery agent

ABSTRACT

The present invention relates to solid compositions comprising a GLP-1 peptide and a delivery agent, such as SNAC, as well as uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/958,236, filed Apr. 20, 2018, which is a Continuation of U.S.application Ser. No. 14/409,021, filed Dec. 18, 2014, which is a 35U.S.C. § 371 National Stage application of International ApplicationPCT/EP2013/062751 (WO 2013/189988), filed Jun. 19, 2013, which claimedpriority of European Patent Application 12172739.0, filed Jun. 20, 2012;this application claims priority under 35 U.S.C. § 119 of U.S.Provisional Application 61/662,456; filed Jun. 21, 2012; the contents ofall above-named applications are incorporated herein by reference.

The present invention relates to solid compositions comprising apharmaceutically active peptide and a delivery agent, which is a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylate (NAC), as well as processes fortheir preparation and uses thereof.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 10, 2021 isnamed 8530US03_SeqList_ST25.txt and is 2 kilobytes in size.

BACKGROUND

One of the main challenges in oral delivery of proteins and peptides isthe inability of these compounds to be readily transported across themembranes of the gastrointestinal tract. The delivery agent SNAC haspreviously been shown to improve the bioavailability of orallyadministered peptides.

WO 2012/080471 A1, WO 2008/109385 A2 and WO 2010/020978 A1 are relatedto oral compositions comprising a peptide drug and a delivery agent.However improved oral compositions are still needed.

The present invention relates to further improvements of thebioavailability by oral administration of compositions of such peptides,in particular of GLP-1 peptides.

SUMMARY

In some embodiments the invention relates to a tablet comprising agranulate comprising i) no more than 15% (w/w) GLP-1 peptide, and ii) atleast 50% (w/w) salt of NAC, wherein said tablet has a) a bulk densityof at least 0.90 g/cm³, b) a median pore diameter of no more than 1.5μm, c) a maximum pore diameter of no more than 4 μm, and/or d) acrushing strength of at least 50 N, wherein said bulk density isdetermined by Assay (Ia) as described herein, wherein said median porediameter or maximum pore diameter is determined by Assay (IIb) asdescribed herein, wherein said crushing strength is determined by Assay(III) as described herein, and wherein said disintegration time isdetermined by Assay (IV) as described herein.

In some embodiments the invention relates to a tablet comprising agranulate comprising i) no more than 15% (w/w) peptide, and ii) at least55% (w/w) salt of NAC, wherein said tablet has a) a bulk density of atleast 0.90 g/cm³, b) a median pore diameter of no more than 1.5 μm, c) amaximum pore diameter of no more than 4 μm, and/or d) a crushingstrength of at least 50 N, wherein said bulk density is determined byAssay (Ia) as described herein, wherein said median pore diameter ormaximum pore diameter is determined by Assay (IIb) as described herein,wherein said crushing strength is determined by Assay (III) as describedherein, and wherein said disintegration time is determined by Assay (IV)as described herein.

In some embodiments the invention relates to a tablet as defined hereinfor use in medicine, such as for treating type 2 diabetes or obesity.

In some embodiments the invention relates to a granulate as definedherein. In some embodiments the invention relates to a process for thepreparation of a tablet comprising a granulate comprising i) no morethan 15% (w/w) peptide, such as GLP-1 peptide, and ii) at least 50%(w/w) salt of NAC, said method comprising the step of exerting acompression force when punching said tablet of at least 5 kN, such as atleast 10 kN or at least 15 kN, or at least 4 kN/cm², such as at least 6kN/cm² or at least 8 kN/cm², wherein said process optionally comprises apre-compression step, and wherein said tablet optionally is as definedherein.

In some embodiments the invention relates to a method for controllingporosity of a group of tablets, said method comprising the steps of: a)determining the near-infrared (NIR) spectrum of one or more of saidtablets; b) comparing said spectrum to a reference NIR spectrum, orperforming a statistical analysis of said spectrum to determine thetablet porosity; c) optionally adjusting the tabletting parametersduring tabletting in order to improve the NIR spectrum or porosity ofthe tablets; and d) selecting a subgroup of tablets with a NIR spectrumor porosity within a predetermined range; wherein said method optionallyis an at-line or an in-line NIR method, and wherein said tabletoptionally is as defined herein.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows surface erosion of Tablet A before (right), after 5 minutes(middle) and after 10 minutes (left) disintegration test.

FIG. 2 shows mercury intrusion into Tablet B (dotted line), Tablet C(broken line) and tablet E (solid line) (poor, medium and goodperforming tablets, respectively).

FIG. 3 shows NIR reflectance spectra of three tablets comprising SNACand Semaglutide with different porosities: 24% (solid line), 15% (dottedline) and 7% (broken line).

FIG. 4 shows correlation between measured tablet porosity and tabletporosity predicted by NIR spectroscopy.

FIG. 5 shows correlation of semaglutide PK profiles with tablet erosionat 1 hour after dosing. <=54% tablet erosion at 1 hour (▪), 55-99%erosion at 1 hour (●), 100% erosion at 1 hour (▴).

FIG. 6 shows correlation of SNAC PK profiles with tablet erosion at 1hour after dosing. <=54% erosion at 1 hour (▪), 55-99% erosion at 1 hour(●), 100% erosion at 1 hour (▴).

DESCRIPTION

The present invention relates to improved tablets comprising a peptide,such as a GLP-1 peptide, and a delivery agent, which is a salt of NAC.The present inventors surprisingly found that the requirements tophysical parameters of tablets, such as density, porosity and/orcrushing strength, as well as the methods of preparation of tabletsaccording to the present invention provide tablets with improvedbioavailability of peptides, such as acylated peptides.

Generally, the term “bioavailability” as used herein refers to thefraction of an administered dose of an active pharmaceutical ingredient(API) and/or active moieties, such as a peptide or a GLP-1 peptide asdefined herein, which reaches the systemic circulation. By definition,when an API and/or active moieties are administered intravenously, itsbioavailability is 100%. However, when it is administered via otherroutes (such as orally), its bioavailability decreases (due toincomplete absorption). Knowledge about bioavailability is importantwhen calculating dosages for non-intravenous routes of administration.

Absolute oral bioavailability is calculated as the relative exposure ofthe API and/or active moieties in systemic circulation following oraladministration (estimated as the area under the plasma concentrationversus time curve) compared to the exposure of the API and/or activemoieties following intravenous administration.

Compositions

The present invention relates to a composition in the form of a tablet.In some embodiments the composition of the invention is for oraladministration.

In some embodiments the tablet comprises a granulate comprising i) nomore than 15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,wherein said tablet has a) a bulk density of at least 0.90 g/cm³; b) amedian pore diameter of no more than 1.5 μm; and/or c) a maximum porediameter of no more than 4 μm. In some embodiments the invention relatesto a tablet comprising a granulate comprising i) no more than 15% (w/w)peptide, and ii) at least 50% (w/w) salt of NAC, wherein said tablet hasa) a bulk density of at least 0.90 g/cm³; b) a median pore diameter ofno more than 1.5 μm; c) a maximum pore diameter of no more than 4 μm;and/or d) a crushing strength of at least 50 N.

In some embodiments the invention relates to a tablet comprising agranulate comprising i) no more than 15% (w/w) peptide, and ii) at least50% (w/w) salt of NAC, wherein said tablet has a) a bulk density, suchas a bulk density, of at least 0.90 g/cm³; b) a median pore diameter ofno more than 1.5 μm; c) a maximum pore diameter of no more than 4 μm; d)a crushing strength of at least 50 N; and/or e) a disintegration time of12-18 minutes for a tablet with a total weight of 300-500 mg comprisingat least 60% (w/w) salt of NAC.

In some embodiments, at tablet of the invention is surface eroding. Bythe term “surface eroding” is herein meant that the material detachmentfrom the tablet is from the surface of the tablet as e.g. depicted inFIG. 1. A surface eroding tablet is thus the opposite of adisintegrating type of a tablet, where the tablet material isdisintegrated into primary particles or granules and hereby acceleratingthe dissolution process.

In some embodiments the term “granulate” refers to one or more granules.In some embodiments the term “granule” refers to particles gathered intolarger particles.

In some embodiments the tablet comprises a granulate comprising apeptide, a salt of NAC and optionally a binder. In some embodiments thecomposition comprises an intragranular and an extragranular part,wherein said extragranular part comprises at least part of a lubricantand optionally a filler.

In some embodiments the tablet comprises less than 15% (w/w) peptide, atleast 50 (w/w) salt of NAC, less than 10% (w/w) binder, 5-40% (w/w)filler, and less than 10 (w/w) lubricant. In some embodiments the tabletcomprises a) a granulate comprising i) 1-15% (w/w) peptide, ii) 55-85%(w/w) salt of NAC, and iii) 1-20% (w/w) binder; b) 10-35% (w/w) filler;and c) 0.5-3% (w/w) lubricant. In some embodiments the tablet comprisesa) a granulate comprising i) 1-100 mg, such as 10 mg, peptide, ii)100-1000 mg, such as 300 mg, salt of NAC, and iii) 1-20 mg, such as 8mg, binder; b) 20-200 mg, such as 100 mg, filler; and c) 0.5-8 mg, suchas 2-8 mg, lubricant.

In some embodiments the invention relates to a granulate as definedherein. In some embodiments the granulate comprises i) no more than 15%(w/w) peptide, and ii) at least 50% (w/w) salt of NAC. In someembodiments the granulate comprises i) 1-15% (w/w) peptide, ii) 55-85%(w/w) salt of NAC, and iii) 1-20% (w/w) binder. In some embodiments thegranulate comprises i) 1-100 mg, such as 10 mg, peptide, ii) 100-1000mg, such as 300 mg, salt of NAC, and iii) 1-20 mg, such as 8 mg,povidone. In some embodiments the granulate comprises at least 80% (w/w)delivery agent, less than 10% (w/w) lubricant, and optionally less than20% filler. In some embodiments the granulate comprises a peptide, atleast 10 (w/w) filler and less than 40% (w/w) binder.

In some embodiments the composition or granulate comprises at least onepharmaceutically acceptable excipient. The term “excipient” as usedherein broadly refers to any component other than the active therapeuticingredient(s). The excipient may be an inert substance, which is inertin the sense that it substantially does not have any therapeutic and/orprophylactic effect per se. The excipient may serve various purposes,e.g. as a delivery agent, absorption enhancer, vehicle, filler (alsoknown as diluents), binder, lubricant, glidant, disintegrant,crystallization retarders, acidifying agent, alkalizing agent,preservative, antioxidant, buffering agent, chelating agent, complexingagents, surfactant agent, emulsifying and/or solubilizing agents,sweetening agents, wetting agents stabilizing agent, colouring agent,flavouring agent, and/or to improve administration, and/or absorption ofthe active substance. A person skilled in the art may select one or moreof the aforementioned excipients with respect to the particular desiredproperties of the solid oral dosage form by routine experimentation andwithout any undue burden. The amount of each excipient used may varywithin ranges conventional in the art. Techniques and excipients whichmay be used to formulate oral dosage forms are described in Handbook ofPharmaceutical Excipients, 6th edition, Rowe et al., Eds., AmericanPharmaceuticals Association and the Pharmaceutical Press, publicationsdepartment of the Royal Pharmaceutical Society of Great Britain (2009);and Remington: the Science and Practice of Pharmacy, 21th edition,Gennaro, Ed., Lippincott Williams & Wilkins (2005).

In some embodiments the composition or granulate comprises a filler,such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose,Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®),microcrystalline cellulose (various grades of Avicel®, Elcema®,Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives,sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins,dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate,calcium carbonate, or sodium alginate. In some embodiments the filler ismicrocrystalline cellulose, such as Avicel PH 101, Avicel PH 102, orAvicel PH 200. In some embodiments the composition comprises 5-40%(w/w), such as 10-30% (w/w) or 5-25% (w/w), filler. In some embodimentssaid filler is in the intragranular and/or extragranular part of thecomposition.

In some embodiments the composition or granulate comprises a binder,such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose,Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®),microcrystalline cellulose (various grades of Avicel®, Elcema®,Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose,L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g.Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps gradesof Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cpsgrades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 gradesof Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A,Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose,ethylcellulose, sodium carboxymethylcellulose, other cellulosederivatives, sucrose, dextrins, maltodextrins, starches or modifiedstarches (including potato starch, maize starch and rice starch),calcium lactate, calcium carbonate, acacia, sodium alginate, agar,carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In someembodiments the binder is povidone, such as povidone K 90. In someembodiments the amount of binder is 0.1-10% (w/w), such as 0.2-4% (w/w)or 0.5-3% (w/w), or such as 1.0-2.5% (w/w). In some embodiments thebinder is in the intragranular and/or extragranular part of thecomposition.

In some embodiments the tablet or granulate does not contain asuperdisintegrant, i.e. an ingredient improving disintegrant efficiencysuch as e.g. sodium starch glycolate, sodium carboxymethyl starch,crospovidone and croscarmellose sodium. In some embodiments thecomposition or granulate comprises a disintegrant, such as alginic acid,alginates, microcrystalline cellulose, hydroxypropyl cellulose, othercellulose derivatives, polacrillin potassium, starch, or pregelatinizedstarch.

In some embodiments the composition or granulate comprises a lubricant,such as stearic acid, magnesium stearate, calcium stearate or othermetallic stearate, talc, waxes, glycerides, light mineral oil, glycerylbehenate, hydrogenated vegetable oils, sodium stearyl fumarate,polyethylene glycols, alkyl sulfates, or sodium benzoate. In someembodiments the composition or granulate comprises a lubricant, such asmagnesium silicate, talc, or colloidal silica. In some embodiments thelubricant is magnesium stearate. In some embodiments the amount oflubricant is 0.1-10% (w/w) or 0.5-5% (w/w), such as 1-3.5% (w/w), 0.5-3%(w/w) or 1.0-2.5% (w/w). In some embodiments the lubricant is in theintragranular and/or extragranular part of the composition.

Still further, the composition or granulate of the invention may beformulated as is known in the art of oral formulations of insulinotropiccompounds.

In some embodiments the weight of the tablet is in the range of 150 mgto 1000 mg, such as in the range of 300-600 mg or such as 300-500 mg.

Methods of Preparation of Pharmaceutical Compositions

In some embodiments the invention relates to a process for thepreparation of a tablet comprising a granulate comprising i) no morethan 15% (w/w) peptide, such as GLP-1 peptide, and ii) at least 50%(w/w) salt of NAC, said method comprising the step of exerting acompression force when punching said tablet of at least 5 kN, such as5-25 kN, and/or at least 4 kN/cm². In some embodiments the compressionforce is in the range of 5-25 kN. In some embodiments the compressionforce is at least 5 kN, such as at least 10 kN or at least 15 kN. Insome embodiments the compression force is no more than 25 kN, such as nomore than 20 kN. In some embodiments the compression force is at least 4kN/cm², such as at least 6 kN/cm² or at least 8 kN/cm². In someembodiments the process comprises a pre-compression step. In someembodiments the tablet or granulate is as defined herein.

The composition of the invention may be prepared as is known in the art.In some embodiments the composition or the granulate may be prepared asdescribed in the examples herein. The composition may comprise one ormore intragranular parts and an extragranular part, wherein theintragranular parts have been granulated, and wherein the extragranularpart has been added after granulation. The extragranular part maycomprise a lubricant.

In some embodiments two or more ingredients of the composition areblended. To prepare a dry blend of tabletting material, the variouscomponents are weighed, optionally delumped and then combined. Themixing of the components may be carried out until a homogeneous blend isobtained.

In some embodiments at least a part of the composition is dry granulatedor wet granulated. A granulate may be produced in a manner known to aperson skilled in the art, for example by dry granulation techniques inwhich the pharmaceutically active agent and/or delivery agents arecompacted with the excipients to form relatively large moldings, forexample slugs or ribbons, which are comminuted by grinding, and theground material serves as the tabletting material to be later compressedinto tablets. Suitable equipment for dry granulation includes but is notlimited to roller compaction equipment from Gerteis, such as GerteisMINI-PACTOR. In some embodiments the granulate is prepared by rollercompaction. In some embodiments the moldings from the roller compactionsprocess are comminuted into granules. Alternatively, a granulate can beobtained by wet granulation which may be carried out by mixing thepharmaceutically active agent dissolved in water with a dry blend of thedelivery agents and optionally one or more excipients followed by dryingof the granulate.

To compress the tabletting material into a solid oral dosage form, forexample a tablet, a tablet press may be used. In a tabletting press, thetabletting material is filled (e.g. force fed or gravity fed) into a diecavity. The tabletting material is then compressed by a punch withpressure. Subsequently, the resulting compact, or tablet is ejected fromthe tabletting press. The above mentioned compression process issubsequently referred to herein as the “compression process”. Suitabletablet presses include, but are not limited to, rotary tablet pressesand eccentric tablet presses. Examples of tablet presses include, butare not limited to, the Fette 102i (Fette GmbH), the Korsch XL100, theKorsch PH 106 rotary tablet press (Korsch AG, Germany), the Korsch EK-Oeccentric tabletting press (KorschA G, Germany), the DIAF TM20 press(Denmark) and the Manesty F-Press (Manesty Machines Ltd., UnitedKingdom). By the term “exerting a compression force” is thus meantcompressing the tabletting material with a specified force as e.g.measured in Newton such as e.g. at least 5 kN or at least 4 kN/cm².

As used herein “pre-compression” is intended to mean the application ofa preliminary compression force just before a second main compressionforce is applied. During the pre-compression step the height of thepowder compact is reduced to no more than 2 times the height of thefinal tablet, such as no more than 2 times or no more than 1.3 times thefinal height of the tablet.

In some embodiments the invention relates to a pharmaceuticalcomposition obtained by the process as defined herein.

In some embodiments the tablet is prepared by exerting a compressionforce in the range of 5-25 kN. In some embodiments the tablet isprepared by exerting a compression force of at least 5 kN, such as atleast 10 kN or at least 15 kN. In some embodiments the tablet isprepared by exerting a compression force of no more than 25 kN, such asno more than 20 kN. In some embodiments the term “resistance to crushingof tablets” or “crushing strength” has the meaning defined in section2.9.8 in the European Pharmacopoeia 7.5, 7th edition 2012; crushingstrength may be measured inter alia in Newton (N) or kilopond (kP) usinga jaw speed of 20 N/s (1 kP equals 9.807 N).

In some embodiments the term “roller compaction force” means the forcebetween the rolls of the roller compactor when compacting materials intoa continuous strip of compressed material as determined by a pressuretransducer that converts the hydraulic pressure into electrical signal;the roller compaction force may be measured in kiloNewton (kN) or inkiloNewton per roll width (kN/cm).

Physical Properties and In Vitro Methods

Density is the ratio of mass to volume. Powder compression is defined asthe reduction of a powder volume due to the application of a mechanicalforce. Bonds are formed between granules during compression because ofthe increased proximity of particle surface accomplished duringcompression, which provide coherence and mechanical resistance to thepowder compact. During compression repacking and deformation of granules(elastic or plastic deformation) will occur. Bulk density is the mass ofthe tablet divided by total volume of the tablet defined by the outerboundary of the tablet. This volume is determined by the dimension ofthe punches (cup volume), die hole surface area and tablet bandthickness used for compression into a tablet. The bulk density can becalculated as (tablet mass/(2×(cup volume)+(die hole surfacearea)×((tablet thickness)−2×(cup depth)))). Alternatively, the bulkdensity can be determined by submerging the tablet into a non-wettingliquid at atmospheric pressure, like mercury, and determining thedisplaced volume. In some embodiments the tablet of the invention has abulk density of at least 0.90 g/cm³, such as at least 0.95 g/cm³ or atleast 1.0 g/cm³, or such as at least 1.1 g/cm³ or at least 1.2 g/cm³. Insome embodiments the bulk density is 1.10-1.19 g/cm³, such as 1.13-1.18g/cm³, such as about 1.14, about 1.15, about 1.16, or about 1.17 g/cm³.In some embodiments the bulk density is no more than 1.19 g/cm³. Bulkdensity of compositions of the invention may be determined as describedin Assay (I) or (IIb) herein.

The microstructure of pharmaceutical solid dosage forms (porosity, porevolume-size distribution, specific surface area) can be investigated bydifferent methods, e.g. mercury porosimetry. Porosity is a measure ofthe void spaces in a tablet, and is a fraction of the volume of voids(i.e. volume of pores) over the total volume, between 0-1, or as apercentage between 0-100%. Porosity can be calculated as (1−(tablet bulkdensity/granule density)) or (1−(tablet bulk density/tablet skeletaldensity)). Alternatively, the pore volume can be determined by mercuryintrusion into the tablet. Since mercury does not wet most substancesand will not spontaneously penetrate pores by capillary action, it mustbe forced into the pores by the application of external pressure. Inpractice, the tablet is evacuated, and then immersed in mercury. Atlaboratory pressures mercury will not enter the pores of the tablet. Thepressure on the mercury is then raised in a stepwise fashion, forcingthe mercury into the pores of the tablet. When the pressure issufficiently high, the mercury will invade all the pores. A measurementof the volume of mercury intruded into the tablets provides the porevolume directly. The pore diameter is the average or effective diameterof the openings in the tablet. There is a direct relation between poresize and amount of mercury intrusion at a given pressure. At anypressure, the pores into which mercury has intruded have diametersgreater than

D=−4γ cos θ/P  (1)

wherein D is the diameter, γ is surface tension of mercury and θ is thecontact angle between the sample and mercury, P is pressure. Bymeasuring the volume of mercury that intrudes into the sample materialwith each pressure change, the volume of pores in the corresponding sizeclass is known. The contact angle of mercury with most solids is between135° and 142°, so an average of 140° can be taken without much error.The surface tension of mercury at 20° C. under vacuum is 480 mN/m. Thenequation 1 can be reduced to:

D=(1470 kPa×μm)/P  (2)

Total intrusion volume (ml mercury per gram of tablet) is the totalvolume on mercury intruded into the sample at the highest appliedpressure and is a measure of pore volume from which porosity can becalculated. The median pore diameter can be determined from thecumulative mercury intrusion volume as the pore diameter where 50% ofthe total volume has been added. The maximum pore diameter can bedetermined from the cumulative mercury intrusion volume as the porediameter where mercury starts to intrude into the sample. In someembodiments the tablet has a median pore diameter of no more than 1.5μm, such as no more than 1.3 μm or no more than 1.0 μm. In someembodiments the tablet has a maximum pore diameter of no more than 4 μm,such as no more than 3.5 μm or no more than 3 μm. Porosity ofcompositions, including median pore diameter and maximum pore diameter,of the invention may be determined as described in Assay (IIa) or (IIb)herein.

Crushing strength of a tablet is the compressive stress (diametrallyapplied) required to cause the tablet to fail by fracture. In someembodiments the tablet has a crushing strength of 50-400 N, such as50-300 N. In some embodiments the tablet has a crushing strength of atleast 50 N, such as at least 75 N or at least 100 N. In some embodimentsthe tablet has a crushing strength of no more than 300 N, such as nomore than 250 N. Crushing strength of compositions of the invention maybe determined as described in Assay (III) herein.

Disintegration time of compositions of the invention may be determinedas described in Assay (IV) herein. In some embodiments the tablet has adisintegration time of 11-18 minutes, such as 12-18 minutes, 12-17minutes or 13-15 minutes. In some embodiments the tablet has adisintegration time of 11-18 minutes, such as 12-18 minutes, 12-17minutes or 13-15 minutes, and wherein said tablet has a total weight of300-500 mg, such as 250-750 mg, and comprises at least 60% (w/w) salt ofNAC. In some embodiments the disintegration time is no more than 22minutes and/or the bulk density is no more than 1.19 g/cm³. In someembodiments the disintegration time is no more than 21 minutes, such asno more than 20 minutes. In some embodiments the tablet of the inventionthe active ingredient(s) and the delivery agent are released by surfaceerosion; hence, the tablets becomes smaller and smaller with time bydissolution primarily from the surface from non-disintegrated tablets.Surface erosion can be shown by visual inspection during thedisintegration test; the tablets are surface eroding if the tablet doesnot break into smaller parts during the first 8 minutes of thedisintegration test.

Dissolution of compositions of the invention may be determined asdescribed in Assay (V) herein. In some embodiments the peptide and thesalt of NAC are co-released from the tablet as determined by Assay (V)as described herein. In some embodiment co-release of two or moreingredients is defined as dissolved relative amounts of said ingredientswithin +/−50%, such as +/−25% or +/−10%, of the ingredient having thehighest dissolved relative amount compared to the ingredient having thelowest dissolved relative amount at any point in time during thedissolution test according to Assay (V) as described herein; wherein thedissolved relative amount is the amount of an ingredient in solutionrelative to the total amount of said ingredient.

Oral bioavailability and absorption kinetics of the composition of theinvention may be determined according to Assay (VI) as described herein.

Cmax is herein used in connection with salt of NAC for the maximumconcentration of salt of NAC in blood plasma after administration andprior to the administration of a second dose, i,e. the peak plasmaconcentration of salt of NAC after administration.

Peptides

In some embodiments the composition of the invention comprises apeptide. In some embodiments the peptide comprises a lipophilic sidechain, such as a peptide comprising an alkyl moiety with at least 14carbon atoms. In some embodiments the peptide is an acylated peptide. Insome embodiments the peptide comprises substituent comprising a fattyacid or a fatty diacid, such as formula (X)

wherein n is at least 13. In some embodiments the peptide comprises oneor more 8-amino-3,6-dioxaoctanoic acid (OEG).

The systemic appearance in plasma of peptides comprising a lipophilicside chain following oral administration is often significantlyprolonged relative to the same peptides without lipophilic side chain.In some embodiments a peptide comprising a lipophilic side chain has aprotracted mode of action. In some embodiments it is particularlyadvantageous when a peptide comprising a lipophilic side chain iscomprised in a tablet of the invention. It has surprisingly been foundby the inventors that a tablet of the invention is particularly suitablewhen the active component is a peptide comprising a lipophilic sidechain. The inventors thus surprisingly found that gradual release of asalt of NAC from the tablet by surface erosion extend the absorptionprofile of a peptide comprising a lipophilic side chain. In someembodiment tablets of the invention cause a gradual release of salt ofNAC leading to a low Cmax in plasma of said salt of NAC in subjects,such as a Cmax of less than 900 ng/ml upon oral administration of atablet comprising approximately 1 mmol salt of NAC.

In some embodiments the amount of peptide is no more than 15% (w/w) orno more than 10% (w/w), such as 1-5% (w/w). In some embodiments thepeptide is in the intragranular part of the composition.

In some embodiments the composition of the invention comprises a GLP-1peptide. The term “GLP-1 peptide” as used herein refers to a compound,which fully or partially activates the human GLP-1 receptor. In someembodiments the “GLP-1 peptide” binds to a GLP-1 receptor, e.g., with anaffinity constant (K_(D)) or activate the receptor with a potency (EC₅₀)of below 1 μM, e.g. below 100 nM as measured by methods known in the art(see e.g. WO98/08871) and exhibits insulinotropic activity, whereinsulinotropic activity may be measured in vivo or in vitro assays knownto those of ordinary skill in the art. For example, the GLP-1 peptidemay be administered to an animal with increased blood glucose (e.g.obtained using an Intravenous Glucose Tolerance Test (IVGTT), a personskilled in the art will be able to determine a suitable glucose dosageand a suitable blood sampling regime, e.g. depending on the species ofthe animal, for the IVGTT) and the plasma insulin concentration measuredover time.

In some embodiments the GLP-1 peptide is a GLP-1 analogue, optionallycomprising one substituent. The term “analogue” as used herein referringto a GLP-1 peptide (hereafter “peptide”) means a peptide wherein atleast one amino acid residue of the peptide has been substituted withanother amino acid residue and/or wherein at least one amino acidresidue has been deleted from the peptide and/or wherein at least oneamino acid residue has been added to the peptide and/or wherein at leastone amino acid residue of the peptide has been modified. Such additionor deletion of amino acid residues may take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide. In some embodimentsa simple nomenclature is used to describe the GLP-1 peptide, e.g.,[Aib8] GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein thenaturally occurring Ala in position 8 has been substituted with Aib. Insome embodiments the GLP-1 peptide comprises a maximum of twelve, suchas a maximum of 10, 8 or 6, amino acids which have been alterered, e.g.,by substitution, deletion, insertion and/or modification, compared toe.g. GLP-1(7-37). In some embodiments the analogue comprises up to 10substitutions, deletions, additions and/or insertions, such as up to 9substitutions, deletions, additions and/or insertions, up to 8substitutions, deletions, additions and/or insertions, up to 7substitutions, deletions, additions and/or insertions, up to 6substitutions, deletions, additions and/or insertions, up to 5substitutions, deletions, additions and/or insertions, up to 4substitutions, deletions, additions and/or insertions or up to 3substitutions, deletions, additions and/or insertions, compared to e.g.GLP-1(7-37). Unless otherwise stated the GLP-1 comprises only L-aminoacids.

In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” asused herein refers to a peptide, or a compound, which is a variant ofthe human Glucagon-Like Peptide-1 (GLP-1(7-37)). GLP-1(7-37) has thesequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In someembodiments the term “variant” refers to a compound which comprises oneor more amino acid substitutions, deletions, additions and/orinsertions.

In some embodiments the GLP-1 peptide exhibits at least 60%, 65%, 70%,80% or 90% sequence identity to GLP-1(7-37) over the entire length ofGLP-1(7-37). As an example of a method for determination of sequenceidentity between two analogues the two peptides [Aib8]GLP-1(7-37) andGLP-1(7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37)relative to GLP-1(7-37) is given by the number of aligned identicalresidues minus the number of different residues divided by the totalnumber of residues in GLP-1(7-37). Accordingly, in said example thesequence identity is (31-1)/31.

In some embodiments the C-terminal of the GLP-1 peptide is an amide.

In some embodiments the GLP-1 peptide is GLP-1(7-37) orGLP-1(7-36)amide. In some embodiments the GLP-1 peptide is exendin-4,the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQID No: 2).

In some embodiments the GLP-1 peptide comprises one substituent which iscovalently attached to the peptide. In some embodiments the substituentcomprises a fatty acid or a fatty diacid. In some embodiments thesubstituent comprises a C16, C18 or C20 fatty acid. In some embodimentsthe substituent comprises a C16, C18 or C20 fatty diacid. In someembodiments the substituent comprises formula (X)

wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. Insome embodiments the substituent comprises formula (X), wherein n is inthe range of 13 to 19, such as in the range of 13 to 17. In someembodiments the substituent comprises formula (X), wherein n is 13, 15or 17. In some embodiments the substituent comprises formula (X),wherein n is 13. In some embodiments the substituent comprises formula(X), wherein n is 15. In some embodiments the substituent comprisesformula (X), wherein n is 17. In some embodiments the substituentcomprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as twoOEG.

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}-ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the GLP-1 peptide is semaglutide, also known asN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),which may be prepared as described in WO2006/097537, Example 4.

In some embodiments the composition comprises the GLP-1 peptide or apharmaceutically acceptable salt, amide, or ester thereof. In someembodiments the composition comprises the GLP-1 peptide one or morepharmaceutically acceptable counter ions.

In some embodiments the dosage of GLP-1 is in the range of 0.01 mg to100 mg. In some embodiments the composition or granulate comprises anamount of a GLP-1 peptide in the range of at least 1 mg, such as atleast 5 mg or at least 10 mg. In some embodiments the composition orgranulate comprises 10 mg GLP-1 peptide.

In some embodiments the composition comprises an amount of a GLP-1peptide in the range of 0.05 to 25 μmol, such as in the range of 0.5 to20 μmol.

In some embodiments the GLP-1 peptide is selected from one or more ofthe GLP-1 peptides mentioned in WO93/19175, WO96/29342, WO98/08871,WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978,WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810,WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050,WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments the GLP-1 peptide is selected from the groupconsisting ofN-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxponadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl-[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)-ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Arg34]GLP-1-(7-37);N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl-[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)-ethoxy]acetylamino)ethoxy]ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37)amide;N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]-[Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}-ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)-acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)-acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)-methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)-acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)-butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Lys26]GLP-1(7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxponadecanoylamino]-methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)-ethoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxponadecanoyl)piperidine-4-carbonyl]amino} propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy] acetylamino) ethoxy] ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino) butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34, Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino} butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy)ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy] acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37] GLP-1-(7-37)amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl][DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy} ethoxy)acetyl][DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1-(7-37)-Glu-Lyspeptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26(17-carboxyhepta-decanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyhamino]methyl}benzoyl[Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide;Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1 H(7-37)-OH;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22, Arg34] GLP-1-(7-37);N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N—((S)-1,3-dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino] ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino} [Aib8,Arg34]GLP-1-(7-37);N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26] GLP-1 (7-37)amide;N-epsilon26-[2-(2-[2-[4-(21-carboxpneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);andN-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxpneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).

In some embodiments the GLP-1 peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]-ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),also known as semaglutide.

Salt of NAC

The delivery agent used in the present invention is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC). In some embodimentsthe delivery agent is an absorption enhancer. The structural formula ofN-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I).

In some embodiments the amount of salt of NAC is at least 50% (w/w) orat least 60% (w/w), such as 50-90% (w/w), 55-85% (w/w) or 70-80% (w/w),or such as 65-75 (w/w), 60-80% (w/w), or 50-90% (w/w). In someembodiments the salt of NAC is in the intragranular part of thecomposition.

In some embodiments the salt of NAC comprises one monovalent cation, twomonovalent cations or one divalent cation. In some embodiments the saltof NAC is selected from the group consisting of the sodium salt,potassium salt and calcium salt of NAC.

The salts of NAC may be prepared using the method described in e.g.WO96/030036, WO00/046182, WO01/092206 or WO2008/028859.

The salt of NAC may be crystalline and/or amorphous. In some embodimentsthe delivery agent comprises any hydrate, solvate and/or anhydrate formof the salt of NAC, such as the anhydrate, monohydrate, dihydrate,trihydrate, a solvate or one third of a hydrate of the salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid as well as combinationsthereof. In some embodiments the delivery agent is a salt of NAC asdescribed in WO2007/121318.

In some embodiments the delivery agent is sodium NAC (referred to as“SNAC” herein), also known as sodium 8-(salicyloylamino)octanoate.

In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)-caprylic acid in the composition is in therange of 0.6-3.5 mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is atleast 0.6 mmol, such as selected from the group at least 0.8 mmol or atleast 0.9 mmol. In some embodiments the amount of the salt of NAC in thecomposition is up to 2.5 mmol. In some embodiments the amount of thesalt of NAC is 1 mmol, such as 1.08 mmol.

In some embodiments the amount of SNAC in the composition is in therange of 100-1000 mg. In some embodiments the amount of SNAC in thecomposition is at least 150 mg, such as or at least 250 mg. In someembodiments the amount of SNAC in the composition is up to 800 mg, suchas up to 700 mg or up to 600 mg. In some embodiments the amount of SNACin the composition is 300 mg.

In some embodiments the molar ratio between the peptide and the salt ofNAC in the tablet is 1:10 or more, i.e. the salt of NAC is in 10 foldexcess of the peptide or more when measured in moles, such as 1:50 ormore, or 1:100 or more.

Method of Controlling Tablet Porosity

In some embodiments the invention relates to a method for controllingporosity of a group of tablets, said method comprising the steps of: a)determining the near-infrared (NIR) spectrum of a selection of tablets,b) comparing said spectrum to a reference NIR spectrum or performing astatistical analysis of said spectrum to determine the tablet porosity,and c) selecting a subgroup of tablets with a NIR spectrum or porositywithin a predetermined range. In some embodiments said method forcontrolling porosity is an at-line NIR method. As used herein, the term“at-line NIR method” is intended to mean a method wherein a NIRspectrometer is placed next to tabletting press and measurement needs anoperator to remove and analyse tablets. In some embodiments said methodfor controlling porosity is an in-line NIR method. As used herein, theterm “in-line NIR method” is intended to mean a method wherein a NIRspectrometer is attached to the tabletting press and measurement isperformed automatically. In some embodiments said method for controllingporosity comprises continuous measurement of porosity. In someembodiments said method for controlling porosity comprises comparison ofsaid spectrum to a reference spectrum. In some embodiments said methodfor controlling porosity comprises adjustment of tabletting parametersduring tabletting in order to improve the porosity of the tablets. Insome embodiments said method for controlling porosity comprisesobtaining a subgroup of tablets with the desired porosity. In someembodiments said method for controlling porosity said tablet is asdefined herein. In some embodiments the term “a group of tablets” isintended to mean at least two tablets, such as at least 10 tablets,5-100 or 20-50 tablets.

Pharmaceutical Indications

The present invention also relates to a composition or a granulate ofthe invention for use as a medicament. In some embodiments thecomposition or the granulate is administered orally.

In particular embodiments, the composition or a granulate of theinvention may be used for the following medical treatments, allpreferably relating one way or the other to diabetes:

(i) prevention and/or treatment of all forms of diabetes, such ashyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetesof the young), gestational diabetes, and/or for reduction of HbA1C;

(ii) delaying or preventing diabetic disease progression, such asprogression in type 2 diabetes, delaying the progression of impairedglucose tolerance (IGT) to insulin requiring type 2 diabetes, and/ordelaying the progression of non-insulin requiring type 2 diabetes toinsulin requiring type 2 diabetes;

(iii) improving β-cell function, such as decreasing β-cell apoptosis,increasing β-cell function and/or β-cell mass, and/or for restoringglucose sensitivity to β-cells;

(iv) prevention and/or treatment of cognitive disorders;

(v) prevention and/or treatment of eating disorders, such as obesity,e.g. by decreasing food intake, reducing body weight, suppressingappetite, inducing satiety; treating or preventing binge eatingdisorder, bulimia nervosa, and/or obesity induced by administration ofan antipsychotic or a steroid; reduction of gastric motility; and/ordelaying gastric emptying;

(vi) prevention and/or treatment of diabetic complications, such asneuropathy, including peripheral neuropathy; nephropathy; orretinopathy;

(vii) improving lipid parameters, such as prevention and/or treatment ofdyslipidemia, lowering total serum lipids; lowering HDL; lowering small,dense LDL; lowering VLDL: lowering triglycerides; lowering cholesterol;increasing HDL; lowering plasma levels of lipoprotein a (Lp(a)) in ahuman; inhibiting generation of apolipoprotein a (apo(a)) in vitroand/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases, such assyndrome X; atherosclerosis; myocardial infarction; coronary heartdisease; stroke, cerebral ischemia; an early cardiac or earlycardiovascular disease, such as left ventricular hypertrophy; coronaryartery disease; essential hypertension; acute hypertensive emergency;cardiomyopathy; heart insufficiency; exercise tolerance; chronic heartfailure; arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis;mild chronic heart failure; angina pectoris; cardiac bypass reocclusion;intermittent claudication (atheroschlerosis oblitterens); diastolicdysfunction; and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases, such asinflammatory bowel syndrome; small bowel syndrome, or Crohn's disease;dyspepsia; and/or gastric ulcers;

(x) prevention and/or treatment of critical illness, such as treatmentof a critically ill patient, a critical illness poly-nephropathy (CIPNP)patient, and/or a potential CIPNP patient; prevention of criticalillness or development of CIPNP; prevention, treatment and/or cure ofsystemic inflammatory response syndrome (SIRS) in a patient; and/or forthe prevention or reduction of the likelihood of a patient sufferingfrom bacteraemia, septicaemia, and/or septic shock duringhospitalisation; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a particular embodiment, the indication is selected from the groupconsisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii),and/or (iii); or indication (v), indication (vi), indication (vii),and/or indication (iix).

In another particular embodiment, the indication is (i). In a furtherparticular embodiment the indication is (v). In a still furtherparticular embodiment the indication is (iix).

In some embodiments the invention relates to a composition or agranulate of the invention for treatment of diabetes or obesity, whereinsaid granulate is administered orally. In some embodiments the inventionrelates to a method for treatment of diabetes or obesity comprising oraladministration of a composition comprising a composition or a granulateof the invention to a patient in need thereof.

The following indications are particularly preferred: Type 2 diabetes,and/or obesity.

Embodiments of the Invention

The following are non-limiting examples of embodiments of the invention:

1. A tablet comprising a granulate comprising i) no more than 15% (w/w)peptide, and ii) at least 50% (w/w) salt of NAC, wherein said tablet has

-   -   a) a bulk density of at least 0.90 g/cm³;    -   b) a median pore diameter of no more than 1.5 μm; and/or    -   c) a maximum pore diameter of no more than 4 μm.        2. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,        wherein said tablet has    -   a) a bulk density of at least 0.90 g/cm³;    -   b) a median pore diameter of no more than 1.5 μm;    -   c) a maximum pore diameter of no more than 4 μm; and/or    -   d) a crushing strength of at least 50 N, such as 50-400 N.        3. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,        wherein said tablet has    -   a) a bulk density, such as a bulk density, of at least 0.90        g/cm³;    -   b) a median pore diameter of no more than 1.5 μm;    -   c) a maximum pore diameter of no more than 4 μm;    -   d) a crushing strength of at least 50 N, such as 50-400 N;        and/or    -   e) a disintegration time of 12-18 minutes for a tablet with a        total weight of 300-500 mg comprising at least 60% (w/w) salt of        NAC.4. A tablet according to any one of the preceding        embodiments, wherein said tablet does not contain a        disintegrant.5. A tablet according to any one of the preceding        embodiments, wherein said disintegration time is no more than 22        minutes and/or said bulk density is no more than 1.19 g/cm³.        6. A tablet according to any one of the preceding embodiments,        wherein said peptide comprises substituent comprising a fatty        acid or a fatty diacid, such as formula (X)

wherein n is at least 13.7. A tablet according to any one of the preceding embodiments, whereinsaid peptide comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG).8. A tablet according to any one of the preceding embodiments, whereinsaid peptide is an acylated peptide or a GLP-1 peptide, such as anacylated GLP-1 peptide.9. A tablet according to any one of the preceding embodiments, whereinsaid tablet is for oral administration.10. A tablet according to any one of the preceding embodiments, whereinthe amount of peptide is no more than 10% (w/w), such as 1-5% (w/w).11. A tablet according to any one of the preceding embodiments, whereinthe amount of said salt of NAC is 50-90% (w/w), such as 55-85% (w/w) or70-80% (w/w).12. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a lubricant, such as magnesium stearate.13. A tablet according to any one of the preceding embodiments, whereinthe amount of said lubricant is no more than 3% (w/w), such as 1.5-3.0%(w/w).14. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a binder, such as povidone.15. A tablet according to any one of the preceding embodiments, whereinsaid granulate comprises a filler, such as microcrystalline cellulose.16. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a granulate comprising said peptide, said salt ofNAC and optionally a binder.17. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises an intragranular and an extragranular part,wherein said extragranular part comprises said lubricant and optionallya filler.18. A tablet according to any one of the preceding embodiments, whereinsaid peptide is a GLP-1 peptide, such as semaglutide.19. A tablet according to any one of the preceding embodiments, whereinsaid salt of NAC is monosodium NAC (SNAC), such as anhydrous SNACmonosodium salt.20. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises

a) a granulate comprising

-   -   i) 1-15% (w/w) peptide,    -   ii) 55-85% (w/w) salt of NAC, and    -   iii) 1-20% (w/w) binder;

b) 10-35% (w/w) filler; and

c) 0.5-3% (w/w) lubricant.

21. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises

a) a granulate comprising

-   -   i) 1-100 mg, such as 10 mg, peptide,    -   ii) 100-1000 mg, such as 300 mg, salt of NAC, and    -   iii) 1-20 mg, such as 8 mg, binder;

b) 20-200 mg, such as 100 mg, filler; and

c) 0.5-8 mg, such as 2-8 mg, lubricant.

22. A tablet according to any one of the preceding embodiments, whereinsaid tablet was prepared by exerting a compression force of at least 5kN, such as at least 10 kN or at least 15 kN, or no more than 25 kN,such as no more than 20 kN or 5-25 kN.23. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a weight of 300-500 mg.24. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a bulk density of at least 0.90 g/cm³, such as at least0.95 g/cm³ or at least 1.0 g/cm³, or such as at least 1.1 g/cm³ or atleast 1.2 g/cm³.25. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a median pore diameter of no more than 1.5 μm, such asno more than 1.3 μm or no more than 1.0 μm.26. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a maximum pore diameter of no more than 4 μm, such as nomore than 3.5 μm or no more than 3 μm.27. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a crushing strength of at least 50 N, such as at least100 N.28. A tablet according to any one of the preceding embodiments, whereinsaid tablet has a disintegration time of 11-18 minutes, such as 12-18minutes, 12-17 minutes or 13-15 minutes, and wherein said tablet has atotal weight of 300-500 mg and comprises at least 60 (w/w) salt of NAC.29. A tablet according to any one of the preceding embodiments, whereinsaid density is determined by Assay (Ia) as described herein.30. A tablet according to any one of the preceding embodiments, whereinsaid median pore diameter or maximum pore diameter is determined byAssay (IIb) as described herein.31. A tablet according to any one of the preceding embodiments, whereinsaid crushing strength is determined by Assay (III) as described herein.32. A tablet according to any one of the preceding embodiments, whereinsaid disintegration time is determined by Assay (IV) as describedherein.33. A tablet as defined in any one of the preceding embodiments for usein medicine.34. A tablet as defined in any one embodiments 1-32 for treating type 2diabetes or obesity.35. A method for treating type 2 diabetes or obesity comprisingadministering a tablet as defined in any one of embodiments 1-32 to apatient in need thereof.36. Use of a tablet as defined in any one of embodiments 1-32 for thepreparation of a medicament.37. Use of a tablet as defined in any one of embodiments 1-32 for thepreparation of a medicament for treating type 2 diabetes or obesity.38. A granulate comprising i) no more than 15% (w/w) peptide, and ii) atleast 50% (w/w) salt of NAC.39. A granulate according to embodiment 38, wherein said granulatecomprises i) 1-5% (w/w) peptide, ii) 55-85% (w/w) salt of NAC, and iii)1-20% (w/w) binder.40. A granulate according to embodiment 38 or 39, wherein said granulatecomprises i) 1-100 mg, such as 10 mg, peptide, ii) 100-1000 mg, such as300 mg, salt of NAC, and iii) 1-20 mg, such as 8 mg, povidone.41. A granulate according to any one of embodiments 38-40, wherein saidgranulate is as defined in any one of embodiments 1-32.42. A process for the preparation of a tablet comprising a granulatecomprising i) no more than 15% (w/w) peptide, such as GLP-1 peptide, andii) at least 50% (w/w) salt of NAC, said process comprising the step ofexerting a compression force when punching said tablet of

-   -   a) at least 5 kN, such as 5-25 kN, or    -   b) at least 4 kN/cm².        43. A process according to embodiment 42, wherein said        compression force is at least 5 kN, such as 5-25 kN, at least 10        kN or at least 15 kN, orb) at least 4 kN/cm², such as at least 6        kN/cm² or at least 8 kN/cm².        44. A process according to embodiment 42 or 43, wherein said        compression force is no more than 25 kN, such as no more than 20        kN.        45. A process according to any one of embodiments 42-44, wherein        said process comprises a pre-compression step.        46. A process according to any one of embodiments 42-45, wherein        said tablet is as defined in any one of embodiments 1-32.        47. A method for controlling porosity of a group of tablets,        said method comprising the steps of:    -   a) determining the near-infrared (NIR) spectrum of a selection        of tablets;    -   b) comparing said spectrum to a reference NIR spectrum, or        performing a statistical analysis of said spectrum to determine        the tablet porosity; and    -   c) selecting a subgroup of tablets with a NIR spectrum or        porosity within a predetermined range.        48. A method according to embodiment 47, wherein said method is        an at-line NIR method.        49. A method according to embodiment 47, wherein said method is        an in-line NIR method.        50. A method according to 49, wherein said method comprises        continuous measurement of porosity.        51. A method according to any one of embodiments 47-50, wherein        said spectrum is compared to a reference spectrum.        52. A method according to any one of embodiments 47-51, wherein        tabletting parameters are adjusted during tabletting in order to        improve the porosity of the tablets.        53. An method according to any one of embodiments 47-52, wherein        a subgroup of tablets with the desired porosity is obtained.        54. A method according to any one of embodiments 47-53, wherein        said tablet is as defined in any one of embodiments 1-32.

Further Embodiments of the Invention

The following are further non-limiting examples of embodiments of theinvention:

1. A tablet comprising a granulate comprising i) no more than 15% (w/w)peptide, and ii) at least 50% (w/w) salt of NAC, wherein said tablet has

-   -   a) a bulk density of at least 0.90 g/cm³;    -   b) a median pore diameter of no more than 1.5 μm; and/or    -   c) a maximum pore diameter of no more than 4 μm.        2. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,        wherein said tablet has    -   a) a bulk density of at least 0.90 g/cm³;    -   b) a median pore diameter of no more than 1.5 μm;    -   c) a maximum pore diameter of no more than 4 μm; and/or    -   d) a crushing strength of at least 50 N, such as 50-400 N.        3. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,        wherein said tablet has    -   a) a bulk density, such as a bulk density, of at least 0.90        g/cm³;    -   b) a median pore diameter of no more than 1.5 μm;    -   c) a maximum pore diameter of no more than 4 μm;    -   d) a crushing strength of at least 50 N, such as 50-400 N;        and/or    -   e) a disintegration time of 12-18 minutes for a tablet with a        total weight of 300-500 mg comprising at least 60% (w/w) salt of        NAC.        4. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 60% (w/w) salt of NAC,        wherein said tablet has    -   a) a bulk density, such as a bulk density, of at least 0.90        g/cm³;    -   b) a median pore diameter of no more than 1.5 μm;    -   c) a maximum pore diameter of no more than 4 μm;    -   d) a crushing strength of at least 50 N, such as 50-400 N;        and/or    -   e) a disintegration time of 12-18 minutes for a tablet with a        total weight of 300-500 mg comprising at least 60% (w/w) salt of        NAC.        5. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC, which        has a bulk density of at least 0.90 g/cm³; wherein said tablet        further has    -   a) a median pore diameter of no more than 1.5 μm; and/or    -   b) a maximum pore diameter of no more than 4 μm.        6. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC, which        has a bulk density of at least 0.90 g/cm³; wherein said tablet        further has    -   a) a median pore diameter of no more than 1.5 μm;    -   b) a maximum pore diameter of no more than 4 μm; and/or    -   c) a crushing strength of at least 50 N, such as 50-400 N.        7. A tablet comprising a granulate comprising i) no more than        15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC, which        has a bulk density of at least 0.90 g/cm³;    -   wherein said tablet further has    -   a) a median pore diameter of no more than 1.5 μm;    -   b) a maximum pore diameter of no more than 4 μm; and/or    -   c) a crushing strength of at least 50 N, such as 50-400 N;        and/or    -   d) a disintegration time of 12-18 minutes for said tablet with a        total weight of 300-500 mg.        8. A tablet according to any one of the preceding embodiments        which is surface eroding.        9. A tablet according to any one of the preceding embodiments,        wherein said tablet does not contain a superdisintegrant.        10. A tablet according to any one of the preceding embodiments,        wherein said tablet does not contain sodium starch glycolate,        sodium carboxymethyl starch, crospovidone or croscarmellose        sodium.        11. A tablet according to any one of the preceding embodiments,        wherein the tablet is dry granulated.        12. A tablet according to any one of the preceding embodiments,        wherein said disintegration time is no more than 22 minutes        and/or said bulk density is no more than 1.19 g/cm³.        13. A tablet according to any one of the preceding embodiments,        wherein said peptide comprises substituent comprising a fatty        acid or a fatty diacid, such as formula (X)

wherein n is at least 13.14. A tablet according to any one of the preceding embodiments, whereinsaid peptide comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG).15. A tablet according to any one of the preceding embodiments, whereinsaid peptide is an acylated peptide or a GLP-1 peptide, such as anacylated GLP-1 peptide.16. A tablet according to any one of the preceding embodiments, whereinsaid tablet is for oral administration.17. A tablet according to any one of the preceding embodiments, whereinthe amount of peptide is no more than 10% (w/w), such as 1-5% (w/w).18. A tablet according to any one of the preceding embodiments, whereinthe amount of said salt of NAC is 50-90% (w/w), such as 55-85% (w/w) or70-80% (w/w).19. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a lubricant, such as magnesium stearate.20. A tablet according to any one of the preceding embodiments, whereinthe amount of said lubricant is no more than 3% (w/w), such as 1.5-3.0%(w/w).21. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a binder, such as povidone.22. A tablet according to any one of the preceding embodiments, whereinsaid granulate comprises a filler, such as microcrystalline cellulose.23. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises a granulate comprising said peptide, said salt ofNAC and optionally a binder.24. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises an intragranular and an extragranular part,wherein said extragranular part comprises said lubricant and optionallya filler.25. A tablet according to any one of the preceding embodiments, whereinsaid peptide is a GLP-1 peptide.26. A tablet according to any one of the preceding embodiments, whereinsaid peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).27. A tablet according to any one of the preceding embodiments, whereinsaid salt of NAC is monosodium NAC (SNAC), such as anhydrous SNACmonosodium salt.28. A tablet according to any one of the preceding embodiments, whereinsaid tablet comprises

-   -   a) a granulate comprising        -   i) 1-15% (w/w) peptide,        -   ii) 55-85% (w/w) salt of NAC, and        -   iii) 1-20% (w/w) binder;    -   b) 10-35% (w/w) filler; and    -   c) 0.5-3% (w/w) lubricant.        29. A tablet according to any one of the preceding embodiments,        wherein said tablet comprises    -   a) a granulate comprising        -   i) 1-100 mg, such as 10 mg, peptide,        -   ii) 100-1000 mg, such as 300 mg, salt of NAC, and        -   iii) 1-20 mg, such as 8 mg, binder;    -   b) 20-200 mg, such as 100 mg, filler; and    -   c) 0.5-8 mg, such as 2-8 mg, lubricant.        30. A tablet according to any one of the preceding embodiments,        wherein said tablet was prepared by exerting a compression force        of at least 5 kN, such as at least 10 kN or at least 15 kN, or        no more than 25 kN, such as no more than 20 kN or 5-25 kN.        31. A tablet according to any one of the preceding embodiments,        wherein said tablet has a weight of 300-500 mg.        32. A tablet according to any one of the preceding embodiments,        wherein said tablet has a weight of 300-400 mg.        33. A tablet according to any one of the preceding embodiments,        wherein said tablet has a weight of about 300 mg.        34. A tablet according to any one of the preceding embodiments,        wherein said tablet has a weight of about 400 mg.        35. A tablet according to any one of the preceding embodiments,        wherein said tablet has a weight of about 430 mg, such as 427        mg.        36. A tablet according to any one of the preceding embodiments,        wherein said tablet has a bulk density of at least 0.90 g/cm³,        such as at least 0.95 g/cm³ or at least 1.0 g/cm³, or such as at        least 1.1 g/cm³ or at least 1.2 g/cm³.        37. A tablet according to any one of the preceding embodiments,        wherein said tablet has a bulk density of no more than 1.2        g/cm³, such as no more than 1.19 g/cm³.        38. A tablet according to any one of the preceding embodiments,        wherein said tablet has a bulk density of about 1.2 g/cm³, such        as about 1.15 g/cm³.        39. A tablet according to any one of the preceding embodiments,        wherein said tablet has a median pore diameter of no more than        1.5 μm, such as no more than 1.3 μm or no more than 1.0 μm.        40. A tablet according to any one of the preceding embodiments,        wherein said tablet has a median pore diameter of about 92 nm.        41. A tablet according to any one of the preceding embodiments,        wherein said tablet has a maximum pore diameter of no more than        4 μm, such as no more than 3.5 μm or no more than 3 μm.        42. A tablet according to any one of the preceding embodiments,        wherein said tablet has a maximum pore diameter of no more than        2.5 μm, such as no more than 2 μm, no more than 1.5 μm, or no        more than 1 μm.        43. A tablet according to any one of the preceding embodiments,        wherein said tablet has a maximum pore diameter of about 0.1 μm.        44. A tablet according to any one of the preceding embodiments,        wherein said tablet has a crushing strength of at least 50 N,        such as at least 100 N.        45. A tablet according to any one of the preceding embodiments,        wherein said tablet has a crushing strength of no more than 400        N.        46. A tablet according to any one of the preceding embodiments,        wherein said tablet has a crushing strength of about 120 N.        47. A tablet according to any one of the preceding embodiments,        wherein said tablet has a disintegration time of 10-18 minutes,        such as 10-17 minutes or 10-13 minutes, and wherein said tablet        has a total weight of 300-500 mg and comprises at least 60%        (w/w) salt of NAC.        48. A tablet according to any one of the preceding embodiments,        wherein said tablet has a disintegration time of 11-18 minutes,        such as 12-18 minutes, 12-17 minutes or 13-15 minutes, and        wherein said tablet has a total weight of 300-500 mg and        comprises at least 60 (w/w) salt of NAC.        49. A tablet according to any one of the preceding embodiments,        wherein said tablet has a disintegration time of 9-11 minutes        for a tablet with a total weight of 300-500 mg and comprises at        least 60% (w/w) salt of NAC.        50. A tablet according to any one of the preceding embodiments,        which causes gradual release of said salt of NAC in vivo.        51. A tablet according to any one of the preceding embodiments,        wherein Cmax in plasma of said salt of NAC is less than 900        ng/ml upon oral administration of said tablet.        52. A tablet according to any one of the preceding embodiments        comprising approximately 1 mmol salt of NAC, wherein Cmax in        plasma of said salt of NAC is less than 900 ng/ml upon oral        administration of said tablet.        53. A tablet according to any one of the preceding embodiments,        wherein said density is determined by Assay (Ia) as described        herein.        54. A tablet according to any one of the preceding embodiments,        wherein said median pore diameter or maximum pore diameter is        determined by Assay (IIb) as described herein.        55. A tablet according to any one of the preceding embodiments,        wherein said crushing strength is determined by Assay (III) as        described herein.        56. A tablet according to any one of the preceding embodiments,        wherein said disintegration time is determined by Assay (IV) as        described herein.        57. A tablet comprising a granulate comprising i) about 5% (w/w)        N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)-acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),        and ii) about 70% (w/w) salt of NAC, wherein said tablet has    -   a) a bulk density of about 1.15 g/cm³;    -   b) a median pore diameter of about 92 nm;    -   c) a maximum pore diameter of about 0.1 μm;    -   d) a crushing strength of about 120 N; and    -   e) a disintegration time of 9-11 minutes for a tablet with a        total weight of about 430 mg, such as 427 mg.        58. A tablet as defined in any one of the preceding embodiments        for use in medicine.        59. A tablet as defined in any one of embodiments 1-57 for        treating type 2 diabetes or obesity.        60. A method for treating type 2 diabetes or obesity comprising        administering a tablet as defined in any one of embodiments 1-57        to a patient in need thereof.        61. Use of a tablet as defined in any one of embodiments 1-57        for the preparation of a medicament.        62. Use of a tablet as defined in any one of embodiments 1-57        for the preparation of a medicament for treating type 2 diabetes        or obesity.        63. A granulate comprising i) no more than 15% (w/w) peptide,        and ii) at least 50% (w/w) salt of NAC.        64. A granulate according to embodiment 63, wherein said        granulate comprises i) 1-5% (w/w) peptide, ii) 55-85% (w/w) salt        of NAC, and iii) 1-20% (w/w) binder.        65. A granulate according to embodiment 63 or 64, wherein said        granulate comprises i) 1-100 mg, such as 10 mg, peptide, ii)        100-1000 mg, such as 300 mg, salt of NAC, and iii) 1-20 mg, such        as 8 mg, povidone.        66. A granulate according to any one of embodiments 63-65,        wherein said granulate is as defined in any one of embodiments        1-57.        67. A granulate according to any one of embodiments 63-65 for        use in a tablet according to any one of embodiments 1-57.        68. A process for the preparation of a tablet comprising a        granulate comprising i) no more than 15% (w/w) peptide, such as        GLP-1 peptide, and ii) at least 50% (w/w) salt of NAC, said        process comprising the step of exerting a compression force when        punching said tablet of    -   a) at least 5 kN, such as 5-25 kN, or    -   b) at least 4 kN/cm².        69. A process according to embodiment 68, wherein said        compression force is at least 5 kN, such as 5-25 kN, at least 10        kN or at least 15 kN, orb) at least 4 kN/cm², such as at least 6        kN/cm² or at least 8 kN/cm².        70. A process according to embodiment 68 or 69, wherein said        compression force is no more than 25 kN, such as no more than 20        kN.        71. A process according to any one of embodiments 68-70, wherein        said process comprises a pre-compression step.        72. A process according to any one of embodiments 68-71, wherein        said tablet is as defined in any one of embodiments 1-57.        73. A method for controlling porosity of a group of tablets,        said method comprising the steps of:

a) determining the near-infrared (NIR) spectrum of a selection oftablets;

b) comparing said spectrum to a reference NIR spectrum, or performing astatistical analysis of said spectrum to determine the tablet porosity;and

c) selecting a subgroup of tablets with a NIR spectrum or porositywithin a predetermined range.

74. A method according to embodiment 73, wherein said method is anat-line NIR method.75. A method according to embodiment 73, wherein said method is anin-line NIR method.76. A method according to 75, wherein said method comprises continuousmeasurement of porosity.77. A method according to any one of embodiments 73-76, wherein saidspectrum is compared to a reference spectrum.78. A method according to any one of embodiments 73-77, whereintabletting parameters are adjusted during tabletting in order to improvethe porosity of the tablets.79. A method according to any one of embodiments 73-78 having a furtherstep between step b) and c), wherein tablet compression force isadjusted based on results from step b) to obtain a group of tables withthe desired porosity.80. A method according to embodiment 79, wherein tablet compressionforce in said further step between step b) and c) is reduced if resultsfrom step b) show that porosity of the tablets is lower than desired, orincreased if results from step b) show that porosity of the tablets ishigher than desired.81. A method according to any one of embodiments 73-78, wherein asubgroup of tablets with the desired porosity is obtained.82. A method according to any one of embodiments 73-81, wherein saidtablet is as defined in any one of embodiments 1-57.

Examples Materials and Methods

The GLP-1 compound semaglutide may be prepared using the methoddescribed in WO2006/097537, Example 4.

The delivery agent SNAC may be prepared using the method described inWO00/046182 or WO2008/028859.

General Methods of Preparation

The manufacturing process of tablets comprised of 3 major unitprocesses, i.e. granulation, blending and compression. The manufacturingprocess additionally comprised a number of secondary unit operationssuch as dry-sieving of granulate and sieving of excipients, which may becarried out according to common general knowledge of a skilled person.

Wet Granulation

For a batch size of 160 tablets (48 g SNAC) typically 13.8 ml water wasused for wet granulation. Approximately 80% (w/w) of the total amount ofwater was filled into a vial and peptide (e.g. GLP-1) was added. Thevial was placed on a Boule mixer, which gently tumbled the vial untilall the material was dissolved. Then pH was adjusted to 8.5 with 1-2 NNaOH solution or 0.2 N HCl solution. Finally, water was added in orderto obtain 100% of the total amount of water.

SNAC and Povidone were blended in a high-shear mixer, such as Diosnahigh-shear mixer or Rowenta mixer, for 1-3 minutes. Then the granulationsolution with dissolved peptide (e.g. GLP-1) was added with a uniformrate over 1-2 minutes using a pipette or syringe. Purified water wasadded if more granulation fluid was needed. The wet granulation wasstopped 10-15 seconds after addition of the granulation solution. Thegranulate was dried in an oven for minimum 16 hours at 45° C. to amoisture content lower than 2.5% as determined by Karl Fisher titrationor loss on drying. The dried granulate was passed through a 0.5 mmsieve.

This method is also referred to as “wet” herein.

Dry Granulation—Method A

Dry granulation was performed by roller compaction of a blend of SNAC,semaglutide, povidone, microcrystalline cellulose and magnesium stearateon a Gerteis Micro-Pactor®. Ribbons were milled with a KitchenAid milland sieved through a 500 μm mesh. The granulated powder was furtherblended with extragranular magnesium stearate (2.3 mg per tablet) for 3minutes on a Turbula mixer before compression into tablets.

This method is also referred to as “dry A” herein.

Dry Granulation—Method B

A blend of SNAC and magnesium stearate in the mass ratio 195:5(SNAC:magnesium stearate) was dry granulated. The remaining magnesiumstearate was added extragranularly during blending subsequent to drygranulation. Dry granulation was carried out by roller compaction on aGerteis MINI-PACTOR using smooth rolls, a 0.63 mm wire mesh screen, anda granulator speed of 60 rpm. The roll speed was set at 1.5 or 3.0 rpmand roller compaction forces around 1 to 13 kN/cm were applied at a gapof 1.0 mm. Subsequent to dry granulation comminution of the moldingsinto granules was carried out.

This method is also referred to as “dry B” herein.

Blending

The granules were blended with extragranular excipients (e.g. filler andlubricant) in several sub-steps before compression. Blending was firstdone with microcrystalline cellulose for 8-10 minutes and then withextragranular magnesium stearate for 3 minutes on a Turbula mixer at 32rpm in an equal volume to volume manner.

Compression

The powder blend was compressed into tablets on e.g. a Fette 102i rotarytablet press, a Korsch PH 100 tablet press, or a DIAF single punchpress. An optional pre-compression step was applied before the maincompression to reduce the amount of entrapped air during the maincompression.

General Methods of Detection and Characterisation Assay (I): Density

The tablet volume and weight was measured. From these measures, the bulkdensity could be calculated as the mass of the tablet divided by thevolume.

Assay (IIa): Calculated Porosity

The tablet volume and weight was measured. From these measures, the bulkdensity could be calculated as the mass of the tablet divided by thevolume. Assuming a skeletal density of the tablet of 1.38 g/cm³ thesolid fraction could be calculated as tablet bulk density divided bytablet skeletal density. The porosity is then 1 minus the solidfraction.

Assay (IIb): Mercury Porosimetry

The porosity analysis utilized a Micromeritics Autopore IV model 9520with Autopore IV 9500 software version 1.06. The sample amount wasadjusted in order to use 10-90% of the stem volume. The sample wasevacuated to 50 μmHg for 5 minutes. The sample cell was then filled withmercury at a filling pressure of 0.0032 MPa, Mercury intrusion wasperformed in the pressure range from 0.0007 to 420 MPa

Assay (III): Crushing Strength

The crushing strength of the tablets was measured with a Pharma Testapparatus (33AA02). The test measures the force required to disrupt thetablet, and the test was based on the pharmacopeia method Ph Eur 2.9.8.

Assay (IV): Disintegration Test

The disintegration test was carried out using a Pharma Test PTZ AUTOdisintegration test apparatus. The setup is based on pharmacopeia methodPh Eur 2.09.01, Test A (Basket-rack assembly). The disintegrationapparatus consists of a basket rack holding 2×6 plastic tubes, open atthe top and bottom, the bottom of the tube is covered by a screen. SNACtablets are placed in the tubes and on top of the tablets are placeddiscs for automated disintegration detection. The basket is immersed in800 ml purified water held at 37° C., in a 1 L beaker. Time for completedisintegration was measured. Furthermore, tablets were observed visuallyfor surface eroding behaviour during the disintegration test.

Assay (V): Dissolution Test

The dissolution test was conducted with apparatus 2 in accordance withUnited States Pharmacopoeia 35 using a paddle rotation speed of 50 rpm.The 500 mL dissolution medium of phosphate buffer (pH 6.8) was used at atemperature of 37° C. The dissolution media had a content of 0.1%Tween80. Sample aliquots were removed at appropriate intervals. Releasewas determined using a RP-HPLC method for dual detection of SNAC andsemaglutide. The content was calculated based on the peak area of theSNAC and semaglutide peaks in the chromatogram relative to the peakareas of the SNAC and semaglutide references, respectively. The HPLCmethod was based on gradient elution on a C8 column. The solvent systemwas trifluoroacetic acid and acetonitrile with UV detection at 210 nm.

Assay (VI): Oral Administration to Beagle Dogs

Animals, Dosing and Blood Sampling: Beagle dogs, weighing 6-17 kg duringthe study period were included in the study. The dogs were dosed infasting state. The compositions were administered by a single oraldosing to the dogs in groups of 8 dogs. Blood samples were taken at thefollowing time points: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4,6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours post dosing. The i.v.solution (20 nmol/mL in a pH 7.4 solution comprising 0.1 mg/ml Tween 20,5.5 mg/ml Phenol, 1.42 mg/ml Na2HPO4 and 14 mg/ml Propylene Glycol) wasdosed in a dose volume of 0.1 mL/kg in the same dog colony in one dosinggroup (n=8). Blood samples were taken at the following time points:predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96,120, 144, 192 and 240 hours post dosing.

Preparation of Plasma: All blood samples were collected into test tubescontaining EDTA for stabilisation and kept on ice until centrifugation.Plasma was separated from whole blood by centrifugation and the plasmawas stored at −20° C. or lower until analysis.

Analysis of Plasma Samples: The plasma was analysed for semaglutideusing a Luminescence Oxygen Channeling Immunoassay (LOCI). The LOCIassay employs donor beads coated with streptavidin and acceptor beadsconjugated with a monoclonal antibody binding to a mid-molecular regionof semaglutide. The other monoclonal antibody, specific for anN-terminal epitope, was biotinylated. In the assay the three reactantswere combined with the semaglutide which form a two-sitedimmuno-complex. Illumination of the complex releases singlet oxygenatoms from the donor beads which channels into the acceptor beads andtrigger chemiluminescence which was measured in the EnVision platereader. The amount of light was proportional to the concentration ofsemaglutide and the lower limit of quantification (LLOQ) in plasma was100 μM.

Example 1: Preparation of Tablets

Tablets comprising GLP-1 and SNAC with compositions as described inTable 1 were prepared by granulation, blending, and compression asdescribed in the section General Methods of Preparation, wherein

-   -   during compression of composition A the compression force was        varied to obtain tablets with varying disintegration times by        adjusting the height of the tablets;    -   tablets from composition D were prepared by direct compression        of a granulate formed by dry granulation by exerting a        compression force of 5.2, 10.2, 14.9, 20.9, or 25.9 kN; and    -   for tablets from composition E a pre-compression step was        applied setting the tablet band height to 3.5 mm, tablets were        prepared by exerting a compression force of 4.0, 5.5, 7.0, or        10.5 kN, and the tablet band height of the final tablets was set        between 1.24 and 1.89 mm.

TABLE 1 Composition of tablets (amounts are expressed as “per tablet”)Composition A B C D E F Semaglutide 10 10 20  10  10 10 (mg) SNAC (mg)300  300 600 300 300 300 Povidone K 90 8-16 8 16  8  8 8 (mg)Microcrystalline 78-156 78 156 100 100 78 cellulose (mg) Magnesium  4 48 7.7 7.7 7.7 Stearate (mg) (intragr.) (intragr.) (intragr.) 2.3 1.6 2.0(extragr.) (extragr.) (extragr.) Sodium na na na na na 1-20 mgpolystyrene sulfonate resin with 1 MBq 111Indium chloride Tablet weight400-498  400 800 428 427 408.7- (mg) 427.7 Granulation type wet wet wetdry A dry B dry B (wet, dry A, or dry B) Tablet tooling 10 13 × 7.5 18.9× 10  10 8.5 × 16 7.5 × 13 (mm) Tablet shape round, oval, oval, round,oval, oval, deep convex convex flat convex convex convex Tablet pressDIAF Korsch Korsch Fette Fette Carver PH 100 PH 100 model CPre-compression no no no no yes no

Example 2: Effect on Tablet Disintegration Time on Oral Bioavailabilityof Semaglutide in Beagle Dogs

Tablets with various crushing strengths and disintegration times wereprepared from composition A as described in Example 1 and with an amountof microcrystalline cellulose and povidone as shown in Table 2. Oralbioavailability and absorption kinetics of GLP-1 after administration ofthe tablets to beagle dogs were determined according to Assay (VI) asdescribed herein. The bulk density was estimated according to Assay (Ia)as described herein. The results are shown in Table 2.

TABLE 2 Oral bioavailability and absorption kinetics of semaglutideafter administration of tablets of composition A with variousdisintegration times to beagle dogs. Content of microcrystalline Contentof Disintegration Oral Estimated cellulose povidone time Total tabletbioavailability Tmax bulk density (mg) (mg) (min:sec) weight (mg) (%)(hours) (g/cm³) 78 8 11:30 416 0.5 0.8 1.02 78 8 13:25 404 1.3 1.5 1.1678 8 14:12 415 2.4 1.2 1.17 120 8 16:34 445 1.0 1.6 1.16 156 16 19:14498 0.2 1.1 1.00 156 16 23:25 497 0.3 1.7 1.20

The results demonstrate that 10 mm round tablets with a deep convex faceand a total weight of 404-445 mg with a disintegration time of 13-17minutes are to be preferred, however, this is expected only to apply fortablets of similar composition and weight, i.e. tablets with a totalweight of 300-500 mg comprising at least 60% (w/w) salt of NAC.

The results further demonstrate that Tmax for plasma semaglutide wasminimum 1 hour for the best performing tablets in contrast to publishedstudies with SNAC and human GLP-1 showing a Tmax of 20-30 minutes.Hence, a somewhat more protracted release of SNAC is desired forpeptides with longer oral absorption half-lives, such as acylated GLP-1peptides.

FIG. 1 shows tablet A before (right), after 5 minutes (middle) and after10 minutes (left) in a disintegration test according to Assay (IV) asdescribed herein on tablets from the batch having an oral availabilityof 2.4% in Table 2. The results show that Tablet A has surface erodingproperties.

Example 3: Porosity Measurements on Good and Poor Performing Tablets

Tablets were prepared from compositions B,C and E (hereafter referred toas Tablet batch B, Tablet batch C and Tablet batch D, respectively) asdescribed in Example 1 and subjected to mercury porosimetry according toAssay (IIb) as described herein. Tablet batch E (comprising 10 mgsemaglutide and 300 mg SNAC) gave the best result in a clinical trial,tablet batch B gave intermediate results, while Tablet batch C(comprising the 20 mg semaglutide and 600 mg SNAC) gave poor resultswith respect to oral bioavailability. The results are shown in Table 3and FIG. 2.

TABLE 3 Porosimetry results from mercury intrusion into Tablet batch B,C and E Tablet Tablet Tablet batch B batch C batch E Total Intrusion0.27 0.41 0.15 Volume (mL/g) Total Pore Area 29.5 24.5 31.6 (m²/g)Median Pore 0.84 2.06 0.09 Diameter (Volume) (μm) Bulk Density at 1.000.88 1.15 0.1000 MPa (g/cm³) Apparent (skeletal) 1.37 1.38 1.38 Density(g/cm³) Porosity (%) 27.1 36.5 17.4

FIG. 2 shows cumulative mercury intrusion into Tablet batch B, C and Edepending on pore diameter. FIG. 2 shows that Tablet batch B has amaximum pore diameter of 2.5 μm whereas Tablet batch C has a maximumpore diameter of 5 μm. FIG. 2 shows a sharp increase in liquid mercuryintrusion volume at a pore diameter of 5 μm for Tablet batch C and amore gradual increase of mercury intrusion at a pore diameter of 2.5 μmfor Tablet batch B, whereas Tablet batch E prepared by a dry granulationtechnique showed low amount of pores above 0.1 μm. This shows thatespecially larger pores are reduced as compression pressure increases,whereas the smaller pores remain intact. Furthermore, dry granulationprovides tablets with very low pore size and porosity.

These results show that preferred tablets providing an improvedbioavailability can be identified by having a porosity of less than36.5%, a bulk density larger than 0.90 g/cm³, a median pore diameterless than 2 μm, and/or a maximum pore diameter less than 5 μm.

Example 4: Compactability of Granulate without a Pre-Compression Step

Tablets were prepared from composition D (round and flat faced tabletswith a diameter of 10 mm) as described in Example 1. The density,porosity, and crushing strength was determined according to Assay (Ia),(IIa), and (III) as described herein, respectively. The results areshown in Table 4.

TABLE 4 Compression profile and resulting tablet properties CompressionCompression Crushing Tablet bulk Porosity pressure pressure/cm² strengthdensity (1-solid (kN) (kN) (N) (g/cm³) fraction) 5.2 6.6 73 1.02 0.2610.2 13.0 156 1.16 0.16 14.9 19.0 197 1.22 0.12 20.9 26.6 221 1.25 0.0925.9 33.0 234 1.27 0.08

These results show that the compression pressure should be higher than5.2 kN or the compression pressure per area should be higher than 6.6kN/cm² in order to obtain tablets with a density above 1.0 g/cm³ and aporosity of no more than 26%.

Example 5: Compactability of a Granulate with a Pre-Compression Step

Tablets were prepared from composition E (16 mm×8.5 mm oval tablets witha convex face) as described in Example 1. Determination of density,porosity, crushing strength, and disintegration time was carriedaccording to Assay (Ia), (IIa), (III), and (IV) as described herein,respectively. The results are shown in Table 5.

TABLE 5 Compression profile and resulting tablet properties CompressionCompression Crushing Disintegration Tablet bulk pressure pressure/cm²strength time density Porosity (kN) (kN) (N) (min:sec) (g/cm³)(fraction) 4.0 3.8 48  9:20 1.08 0.22 5.5 5.2 75 11:30 1.21 0.12 7.0 6.695 12:00 1.20 0.13 10.5 9.9 135 12:30 1.30 0.06

The results show that SNAC tablets with low porosity (<37%) and highdensity (>1.0 g/cm³) can be prepared at a compression pressure >4.0 kNor at a compression pressure per area of more than 3.8 kN/cm² when apre-compression step is included in the tabletting step.

Example 6: Control of Tablet Porosity by Near-Infrared (NIR) ReflectanceSpectroscopy

NIR reflectance has been demonstrated to be a fast and precise method tocontrol the porosity of tablets comprising SNAC and Semaglutide. Tabletswith varying porosity were manufactured by varying the compression forceas described in Example 4. A NIR reflectance spectrum was acquired froma group of tablets from each of the applied compressions forces byscanning twice on each side with a Bruker MPA 01 Multi Purpose FT-NIRAnalyzer. Subsequently, the spectrum was compared to the porosity valuefor the tablet, which was determined as described in Example 4, usingprojections to latent structures (PLS) regression.

FIG. 3 shows the NIR reflectance spectrum of three tablets with porosityof 24%, 15 and 7%. At wavelengths from 12.000 cm⁻¹ to 6.000 cm⁻¹ is thespectral absorbance increasing with increasing porosity. At wavelengthsfrom 5.000 cm⁻¹ to 4.000 cm⁻¹ is the spectral absorbance decreasing withincreasing porosity.

A statistical regression model was established between the spectra offifty tablets comprising SNAC and Semaglutide and their correspondingporosity values. With such a regression model is it possible to predictthe porosity of future tablet samples based on their NIR reflectancespectrum. The results are shown in FIG. 4 where tablet porosity values(x-axis) for the fifty tablets comprising SNAC and Semaglutide werecompared to the tablet porosity predicted by the regression model(y-axis) based on the NIR reflectance spectrum. There was found to be ahigh correlation between the two methods (R²=0.99).

Accordingly, this method provides a fast and easy determination oftablet porosity on individual tablets with NIR spectroscopy duringtabletting. This allows NIR spectroscopy to be used for in-linemonitoring of porosity of individual tablets and for adjustment of thetabletting process to achieve tablets with a highly specific porosity.

Furthermore, based on these results it is possible to interface NIRtechnology with the tabletting machine in three distinct ways andthereby enable real-time control of tablet porosity during tabletting(Table 6).

TABLE 6 Interface opportunity. Interface opportunity InstrumentationControl At-line, Off-the shelf NIR The spectrometer is fullspectrometer. placed next to the spectrum Analysis time ~10- tablettingpress. 20 seconds/tablet During the tabletting plus sample removalprocess are samples and time for manual removed, analysed and controladjustments. the porosity determined. Commercially available. Theoperator can adjust the tabletting press to optimize the porosity duringmanufacturing. In-line, The NIR spectrometer The spectrometer pc is fullis attached to the interfaced with the spectrum tabletting press. Atabletting press and robotic arm removes signals for adjustment samplesand places of the tabletting press them in the NIR is transferredspectrometer for automatically to analysis. optimize the porosityAnalysis time ~30 during manufacturing seconds/tablet. Commerciallyavailable. In-line, The tablets pass a The spectrometer pc is singlemeasuring point when interfaced with the wavenumber leaving thetabletting tabletting press and press. A light emitting signals foradjustment diode (LED) based of the tabletting press instrument measuresis transferred the NIR reflectance at automatically to one specificwavelength optimize the porosity from the surface of the duringmanufacturing tablets as they pass the measuring point. Analysis time ~milliseconds. Not commercially available. Needs to be designed.

Example 7: Dissolution of Tablets

Tablets were prepared from compositions B and C (hereafter referred toas Tablet batch B and Tablet batch C, respectively) as described inExample 1 and their dissolution profile was determined according toAssay (V) as described herein. The results are shown in Table 7.

TABLE 7 Dissolution profile Tablet batch B Tablet batch C Time fromSemaglutide SNAC Semaglutide SNAC test start (% (w/w) of (% (w/w) of (%(w/w) of (% (w/w) of (min) 10 mg) 300 mg) 20 mg) 600 mg) 15 62 65 63 6230 86 87 105 100 45 91 90 106 100 60 93 92 106 100

These results show that GLP-1 and SNAC are co-released in Tablet batch Band Tablet batch C.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

Example 8: In Vivo Location and Duration of Tablet Erosion

The in vivo location and duration of tablet erosion was investigated ina clinical study using gamma-scintigraphy. The study also assessed thepharmacokinetic parameters of oral semaglutide and SNAC. In order toemploy gamma scintigraphy, a gamma emitting isotope was incorporatedinto formulation F (Table 1), where indium-111 (111In) was used to labela sodium polystyrene sulfonate resin, which was incorporated into thetablets.

Manufacturing Process

The manufacturing process was a three-stage process whereby simpleblending was undertaken to prepare the SNAC/magnesium stearate blend,the Amberlite® resin was radiolabelled and the final tablet wascompressed by individually weighing out the aforementioned components aswell as the semaglutide granules.

The SNAC/magnesium stearate blend was prepared by manual volumetricdoubling of the magnesium stearate with the SNAC granules, followed byblending using an inflated plastic bag. Magnesium stearate waspre-screened before use through a 355 μm sieve.

Before compression the lubricated SNAC blend, semaglutide granules andradiolabelled Amberlite® IRP-69A resin were individually weighed out foreach tablet and manually mixed until visually uniform.

The radiolabelled tablets were compressed using a manual Carver Model Ctablet press (L145) at a compression force of 6.7 kN (8.8 kN/cm²).Tablets were compressed with a 7.5×13 mm radial oval convex tablettooling. The tablet thickness was 6.4 mm. Hardness varied from 91-104 N,and bulk density was 1.07 g/cm³

Dosing

24 Subjects were treated in a cross-over trial design so that allsubjects received one period with dosing of 10 mg semaglutide and 50 mlwater and one period with dosing of 10 mg semaglutide and 240 mL water.Dosing was performed with the subjects positioned in a sitting positionin front of the gamma camera to provide an anterior view and permitmeasurement of oesophageal transit. Blood samples for pharmacokineticprofiles were collected and the pharmacokinetic assessments included24-hours semaglutide profiles and 6-hours SNAC profiles. Scintigraphydynamic imaging was performed (until 4 hour post-dosing) and safety andtolerability was assessed. The dynamic imaging was performed with thesubjects sitting. Subjects remained in the camera room until completionof the rapid imaging phase (30 minutes post-dose). Static imaging wasperformed with subjects standing. Thereafter, subjects were permitted toleave the camera room. Subjects were permitted to sit or remainmoderately active (walk around the clinical unit) and imaging continueduntil 4 hours post dosing. Initial tablet erosion (ITE) was defined asthe first sign of sustained release of radioactive marker from thetablet. Complete tablet erosion (CTE) was defined as the time at whichthe entire radioactive marker had dispersed into the gastrointestinaltract and no signs of a distinct ‘core’ remain. The anatomical locationof the capsule at the time of each event (ITE and CTE) was determined.Quantitative assessment of tablet erosion was performed to generate thetablet erosion time profile. A region of interest was drawn around thetablet and amount of radioactive marker retained within that region wasquantified. Data was corrected for depth of radioactivity in the body,radioactive decay and background.

Blood samples were collected at −30, 0, 10, 20, 30, 40, 50 minutes, 1,1.5, 2, 3, 4, 6 12 and 24 hours post dosing. Bioanalysis of semaglutidewas performed using a validated assay and bioanalysis of SNAC wasperformed using a liquid chromatography mass spectrometry (LC/MS/MS)assay.

TABLE 8 Tablet erosion of tablets after dosing with 50 or 240 ml water50 ml*⁾ 240 ml*⁾ Time (min) to initial 6.0 (7.7) 9.7 (18.4) tableterosion (SD) (min post-dose) Time (min) to complete 95.4 (49.4) 66.2(48.8) tablet erosion (SD) Duration (min) of 89.9 (48.8) 56.4 (43.1)tablet erosion (SD) *⁾Standard deviation shown in brackets

The anatomical location of ITE and CTE was the stomach for all subjects,for both volumes of water tested. The duration of tablet erosion was tosome degree influenced by water volume, however even with a large volumeof water the duration of tablet erosion was surprisingly long (56±43minutes). The long erosion time is a central aspect of the tablettechnology.

A negative correlation between tablet erosion at 1 hour post dosing andsemaglutide plasma exposure is shown in FIG. 5. Full tablet erosion at 1hour resulted in very low plasma exposure of semaglutide, whereas lessthan 54% tablet erosion resulted in high plasma exposure of semaglutide.It is seen that slow tablet erosion correlated with higher plasmasemaglutide exposure and longer tmax of semaglutide.

FIG. 6 shows that a higher degree of tablet erosion for a tabletcontaining 300 mg SNAC at 1 hour after dosing correlated with higherpeak exposure to SNAC. Hence, plasma exposure and Cmax of SNACcorrelated negatively with the efficacy of the tablet.

1. A tablet comprising a granulate comprising: i) no more than 15% (w/w)GLP-1 peptide, and ii) at least 50%, 55%, or 60% (w/w) salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC).
 2. A tablet accordingto claim 1, wherein said peptide comprises a substituent comprising afatty acid or a fatty diacid, of formula (X)

wherein n is at least 13; and wherein said peptide optionally comprisesone or more 8-amino-3,6-dioxaoctanoic acid (OEG).
 3. A tablet accordingto claim 1, wherein said GLP-1 peptide is semaglutide.
 4. A tabletaccording to claim 1, wherein said salt of NAC is monosodium NAC (SNAC),anhydrous SNAC monosodium salt.
 5. A tablet according to claim 1,wherein the amount of said salt of NAC is 50-90% (w/w), 55-85% (w/w), or70-80% (w/w).
 6. A tablet according to claim 1, wherein said tabletcomprises an intragranular and an extragranular part, wherein saidextragranular part comprises a lubricant and optionally a filler.
 7. Atablet according to claim 1, wherein said tablet comprises a) agranulate comprising i) 1-15% (w/w) GLP-1 peptide, ii) 55-85% (w/w) saltof NAC, and iii) 1-20% (w/w) binder; b) 10-35% (w/w) filler; and c)0.5-3% (w/w) lubricant.
 8. A tablet according to claim 1, wherein saidtablet does not comprise a superdisintegrant.
 9. A tablet according toclaim 1, wherein said tablet is for oral administration.
 10. A tabletaccording to claim 1, wherein said tablet was prepared by exerting acompression force of at least 5 kN, such as 5-25 kN, at least 10 kN orat least 15 kN, or at least 4 kN/cm², such as at least 6 kN/cm² or atleast 8 kN/cm².
 11. A method of treating type 2 diabetes or obesitycomprising administering to a subject in need of such treatment a tabletaccording to claim
 1. 12. A process for the preparation of a tabletcomprising a granulate comprising i) no more than 15% (w/w) GLP-1peptide, and ii) at least 50% (w/w) salt of NAC, said method furthercomprising the step of exerting a compression force when punching saidtablet of a) at least 5 kN, such as 5-25 kN, at least 10 kN or at least15 kN, and/or b) at least 4 kN/cm², such as at least 6 kN/cm² or atleast 8 kN/cm², wherein said process optionally comprises apre-compression step.
 13. A method for controlling porosity of thetablet of claim 1, said method comprising the steps of: a) determiningthe near-infrared (NIR) spectrum of one or more of said tablets, b)comparing said spectrum to a reference NIR spectrum or performing astatistical analysis of said spectrum to determine the tablet porosity,c) optionally adjusting the tabletting parameters during tabletting inorder to improve the NIR spectrum or porosity of the tablets, and d)selecting a subgroup of tablets with a NIR spectrum or porosity within apredetermined range, wherein said method optionally is an at-line or anin-line NIR method.